Infections caused by Staphylococcus aureus, methicillin resistant Staphylococcus aureus (MRSA) and related gram positive pathogens are growing and continuous medical concern. Vancomycin and other glycopeptide antibiotics, are currently the agents of choice for combating these infections which are predominantly encountered in hospital settings. With the increased usage of Vancomycin, resistant strains have been found and are referred to as vancomycin intermediate-resistant Staphylococcus aureus (VISA). Schito, G. C., The Importance of the Development of Antibiotic Resistance in Staphylococcus Aureus, Clin. Microbiol. Infect., 2006, 12 Suppl. 1:3-8. Additionally, there is currently an epidemic of community-acquired MRSA (CA-MRSA) pneumonia in this country, which is reportedly linked to Staphylococcus aureus (SA) infection. Hageman, J. C., et al., Severe Community-Acquired Pneumonia Due to Staphyloccus aureus, 2003-04 Influenza Season, Emerg. Infect. Dis. 2006, available at the Centers for Disease Control website. Consequently, there is a dire need to develop new structural entities with a new mode of action against MSRA, other nosocomial and CA-MRSA opportunistic infections.
Furthermore, infections caused by opportunistic pathogens such as Cryptococcus neoformans (Cn or C. neoformans), Candida albicans (Ca or C. albicans), Aspergillus fumigatus (Af or A. fumigatus) are growing medical concerns for immunucompromised patients such as those with AIDS. If not properly treated, these mycotic infections are often fatal. Despite tremendous progress in the development of new antifungal agents, drugs currently on the market including Amphotericin B in combination with Flucytosine and azoles present serious limitations. Echinocandins, the newest antifungal agents are fungistatic against clinically relevant Aspergillus species and are resistant in vitro to Cryptococcus and Zygomycetes. Thus, with the rising incidence of systemic mycoses due to immunosuppresion and neutropenia, there is an urgent need to develop novel systemic antifungal drugs.
It has been reported that cryptolepine and other alkyl substituted indolo[3,2-b]quinolines, also referred to as quindolines constitutes an important structural moiety in the literature because it possesses antiinfective activity against some opportunistic infectious organisms. Etukala, J. R.; Suresh Kumar, E. V. K.; Ablordeppey, S. Y., A Short and Convenient Synthesis and Evaluation of the Antiinfective Properties of Indoloquinoline Alkaloids: 10H indolo[3,2-b]quinoline and 7H-indolo[2,3-c]quinolines. J. Heterocycl Chem., 2008, 45, 507-511, Ablordeppey S. Y.; Fan, P.; Li, S.; Clark, A. M.; Hufford, C. D, Substituted Indoloquinolines as New Antifungal Agents, Bioorganic and Medicinal Chemistry, 2002, 10, 1337-1346. Zhu, et al., Synthesis and Evaluation of Isosteres of N-Methyl indolo[3,2-b]-quinoline (cryptolepine) as New Antiinfective Agents, Bioorg. Med. Chem., 2007, 15, 686-695. However, the action of these compounds appears to operate through intercalation to DNA. Bonjean, K., et al., The DNA Intercalating Alkaloid Cryptolepine Interferes With Topoisomerase II and Inhibits Primarily DNA Synthesis in B16 Melanoma Cell, Biochemistry, 1998, 37, 5236-5146. PCT/US2007/007976 referenced various publications showing that alkylation of nitrogen at the 5-position with omega-phenylpentyl and omega-cyclohexylpentyl groups produced high antifungal potency and broadened the spectrum of activities.
The present invention relates to novel 3-substituted quinolinium and 7H-indolo[2,3-c]quinolinium antiinfective compounds, which are ring-opened and angular quindoline analogs/isosteres that are capable of entering the cells and more importantly in crossing the blood-brain barrier to elicit anti-infective actions. These novel 3-substituted quinolinium antiinfectives have been shown to be more potent, yet less toxic than the parent tetracyclic quindoline. The angular quindolinium compounds have been shown to have better anti-MRSA, anti-cryptococcal and cytoxicity profiles than those of the linear quindolinium salts represented by cryptolepine. The antiinfectives of the present invention thus comprise an important contribution to therapy for treating infections caused by difficult to control pathogens. There is an increasing need for agents effective against pathogens such as MRSA, C. neoformans, and other fungal pathogens and protozoa which are at the same time relatively free from undesirable side effects.